1. Field of the Invention
The present invention relates to compositions and methods for increasing the concentration and/or motility of spermatozoa in humans, including compositions and methods for treating humans affected by idiopathic asthenozoospermia.
2. Description of the Prior Art
Spermatozoa are produced in the testis and undergo post-gonadal modifications in the epididymis to acquire fertilizing ability. In epididymal plasma, high-molecular-weight proteins and such small molecules as free carnitine convert the gametes into "competent" and functional cells. Free L-carnitine is taken up from blood plasma and concentrated in the epididymal lumen. This epididymal secretion is beneficial for spermatozoa and is not merely an excretory waste. Free carnitine goes through the sperm plasma membrane by passive diffusion. Free L-carnitine is acetylated in mature spermatozoa only. The excess acetyl-CoA from the mitochondria is probably stored as acetyl-L-carnitine and modulates the reserves of free CoA essential to the function of the tricarboxylic acid cycle. This property of L-carnitine of buffering CoA in the mitochondrial matrix is known in somatic cells but is accentuated in male germinal cells. The relationship between the endogenous pool of free and acetylated L-carnitine and the percentage of progressive sperm motility indicates a more important metabolic function related to flagellar movement. Thus, the potential of initiating sperm motility which takes place in the epididymis is probably independent of the carnitine system while the energy properties of acetyl-L-carnitine is relevant in situations of "energy crisis". The uptake of cytoplasmic free L-carnitine in mature spermatozoa must be a protective form of mitochondrial metabolism useful to the survival of this isolated cell.
Idiopathic asthenozoospermia, a disorder of sperm motility, is illustrative of certain conditions in this area. It is a post-testicular cause of infertility due to various ethiology, i.e. congenital defects of the sperm tail, maturation defects, immunological disorders or infection. Several drugs for treating idiopathic asthenozoospermia, none of them completely satisfactory, are known.
Antiestrogen drugs (such as clomiphene citrate and tamoxifen) block sex hormones from inhibiting the Follicle Stimulating Hormone (FSH) and the Luteinizing Hormone (LH) in the brain. This triggers an increased release of LH and FSH, which in turn stimulates testosterone production. Increased testosterone level improves spermatogenesis, thus improving sperm density and motility. However a recent randomized, double-blind, multicenter study of 190 couples by the World Health Organization (WHO) showed no effect of clomiphene citrate. Tamoxifen was claimed to improve sperm concentration but no change in motility was usually detected. As for clomiphene, recent studies did not confirm its efficacy.
Testosterone Rebound therapy involves large doses of testosterone that suppress the activity of the patient's pituitary gland. This, in turn, reduces the intratesticular level of testosterone to systemic levels from the usual level. Then the androgen therapy is discontinued in the hope that the system will rebound and improved spermatogenesis will result.
This therapy is not recommended since a large number of treated patients continue to exhibit azoospermia after treatment.
Testolactone, an aromatase inhibitor, prevents the conversion of testosterone to estradiol. It has been tested in patients with idiopathic oligospermia but contrasting results have raised many doubts on its efficacy.
Mesterolone is a synthetic androgen widely used to treat idiopathic male infertility. A recent study sponsored by WHO failed to show any efficacy of this drug.
Human Chorionic Gonadotropin (HCG) is administered empirically to patients with defects in sperm count or motility to correct a presumed intratesticular deficiency of testosterone. Some patients actually experienced a depression of sperm count due to an increased estrogen production by the testes.
Human Menopausal Gonadotropin (HMO) has approximatively equal LH and FSH activity but its use has produced increased sperm counts in only about 50% of cases.
FSH and HCG or HCG and HMG combination therapy does not appear to improve these results any better.
Gonadotropin Releasing Hormone (GnRH) is expensive and disappointing results have been obtained.
Kallikrein can improve sperm motility with increases in sperm concentration but only in about 50% of cases.
Also L-carnitine and acetyl L-carnitine have been studied as candidate drugs for the treatment of asthenospermia.
Vitali G. et al. (Drugs Exptl. Clin. Res. XXI(4):157-159, 1995) investigated the effectiveness of L-carnitine administration in a group of patients with idiopathic asthenospermia. A favourable effect of the compound on sperm motility and rapid linear progression has been shown in 37 out of 47 patients treated. Same results were obtained by Torok L. (Dermatol. Monatsschr. 169:572-575, 1983).
Costa M. et al. (Andrologia, 26: 155-159, 1994) showed a significant improvement, both in a quantitative and qualitative manner, in spermatozoa! motility after administration of L-carnitine. They speculated that in infertile patients impairment occurred either in epididymal function or in the ability of sperm to capture and utilize carnitine (Bartelloni M. et al., Acta Eur. Fertil. 18:29-31, 1987). Thus, the administration of carnitine would provide additive substrate for sperm energy metabolism and motility.
Muller-Tyl E. et al. (Fertilitat 4:1-4, 1988) suggested that L-carnitine therapy can be successful in infertile patients. In fact, results demonstrated a continuous increase in the carnitine levels in sperm following carnitine treatment and a contemporary increase in motility and sperm cell count.
Loumbakis P. et al. (XIIth Congress of the European Association of Urology. Paris, Sep. 1-4, 1996) provided preliminary data suggesting that carnitine administration may positively affect sperm quality.
Finally, Moncada M. L. et al. (Acta Eur. Fertil. 23(5):221-224, 1992) investigated the effect on sperm quality of acetyl-L-carnitine administered to patients affected by idiopathic oligoasthenospermia. Acetyl-L-carnitine had no effects on sperm density, but showed to increase progressive sperm motility.